Microsomal mixed-function oxidases

Ritter CL, Malejka-Giganti D. 1982. Mixed function oxidase in the mammary gland and liver microsomes of lactating rats. Biochem Pharmacol 31 239-247. 

A potentially powerful probe for sorting out the contribution of hydroperoxide-dependent and mixed-function oxidase-dependent polycyclic hydrocarbon oxidation is stereochemistry. Figure 9 summarizes the stereochemical differences in epoxidation of ( )-BP-7,8-dihydrodiol by hydroperoxide-dependent and mixed-function oxidase-dependent pathways (31,55,56). The (-)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (+)-anti-diol epoxide by both pathways whereas the (+)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (-)-anti-diol epoxide by hydroperoxide-dependent oxidation and to the (+)-syn-diol epoxide by mixed-function oxidases. The stereochemical course of oxidation by cytochrome P-450 isoenzymes was first elucidated for the methycholanthrene-inducible form but we have detected the same stereochemical profile using rat liver microsomes from control, phenobarbital-, or methyl-cholanthrene-induced animals (32). The only difference between the microsomal preparations is the rate of oxidation. 

Lipid-soluble xenobiotics are commonly biotra ns formed by oxidation in the drug-metabolizing microsomal system (DMMS). For each description below, choose the component of the microsomal mixed-function oxidase system with which it is most closely associated ... 

Diarrhea, reduced food and water consumption, body weight loss, decreased blood glucose levels, and disrupted hepatic microsomal mixed function oxidases in mice receiving 10 mg/kg body weight daily (Fujimori et al. 1983). 

Many commercial lots of technical PCP are known to contain small — but possibly biologically significant — amounts of highly toxic dioxins, dibenzofurans, and hexachlorobenzene. These contaminants may be responsible for most of the toxicity of technical PCP preparations (McConnell et al. 1980 Parker et al. 1980 Wollesen et al. 1986 Holsapple et al. 1987). However, both technical-and analytical-grade PCP can induce hepatic mixed-function oxidases in intoxicated rats and cattle. In cattle, this effect was observed in both calves and adults, and in hepatic as well as pulmonary microsomes, and seemed to be dose related (Shull et al. 1986). 

Shull, L.R., B.A. Olson, B.J. Hughes, R.M. McKenzie, and J.H. Kinzell. 1986. Effect of pentachlorophenol on microsomal mixed-function oxidases in cattle. Pest. Biochem. Physiol. 25 31-39. 

Arinc, E. and A. Sen. 1994. Effects of in vivo benzo[a]pyrene treatment on liver microsomal mixed-function oxidase activities of gilthead seabream (Sparus aurata). Comp. Biochem. Physiol. 107C 405-414. 

Fabacher, D.L. and P.C. Baumann. 1985. Enlarged livers and hepatic microsomal mixed-function oxidase components in tumor-bearing brown bullheads from a chemically contaminated river. Environ. Toxicol. Chem. 4 703-710. 

Liver necrosis is another concern following hexachloroethane exposure. Hexachloroethane is metabolized in the centrilobular area of the liver by way of the microsomal mixed function oxidase system. The relatively nonpolar pentachloroethyl free radical is an intermediate in this pathway. The reaction of the free radical with unsaturated lipids in the cellular or organelle membranes could contribute to hepatocyte damage and necrosis. 

Environmental agents that influence microsomal reactions will influence hexachloroethane toxicity. The production of tetrachloroethene as a metabolite is increased by agents like phenobarbital that induce certain cytochrome P-450 isozymes (Nastainczyk et al. 1982a Thompson et al. 1984). Exposure to food material or other xenobiotics that influence the availability of mixed function oxidase enzymes and/or cofactors will change the reaction rate and end products of hexachloroethane metabolism and thus influence its toxicity. 

Knights KM, Gourlay GK, Cousins MJ. Changes in rat hepatic microsomal mixed function oxidase activity following exposure to halothane under various oxygen concentrations. Biochem Pharmacol 1987 36(6) 897-906. 

Freudenthal, R., Leber, P., Emmerling, D., Kerchner, G. and Campbell, D. (1976). Characterization of the hepatic microsomal mixed-function oxidase system in miniature pigs. Drug Metab. Dispos. 4 25-27. 

Madhukar BV, Matsumura F. 1979. Comparison of induction patterns of rat hepatic microsomal mixed-function oxidases by pesticides and related chemicals. Pestic Biochem Physiol 11(1-3)301-308. 

Peppriell J. 1981. The induction of hepatic microsomal mixed-function oxidase activities in the mouse by mirex, 3,4,5,3 ,4 ,5 -hexachlorobiphenyl, and equimolar dosages of both. Environ Res 26 402-408. 

Hildebrandt A., Estabrook RW. 1971. Evidence for the participation of cytochrome b5 in hepatic microsomal mixed-function oxidase reactions. Arch Biochem Biophys 143 66-79. 

Stevens JT, Greene FE, Stitzel RE, et al. 1973. Effects of anticholinesterase insecticides on mouse and rat liver microsomal mixed function oxidase. In Deichmann W.B., Ed. Pesticides and the environment A continuing controversy. Proceedings of the 8th Inter-American Conference on Toxicology and Occupational Medicine, University of Miami School of Medicine, 489-501. 

The desaturation process is particularly interesting as it provides an example of a microsomal (as opposed to mitochondrial) electron transport system. The enzymes responsible, fatty acyl-CoA desaturases, are examples of mixed function oxidases... 

Enzymes of the hepatic microsomes of most marine organisms, with the notable exception of certain molluscs, metabolize xeno-biotic substrates however, as much as 600-fold variations in enzyme activities have been noted between different species of marine teleosts (40). The hepatic enzyme activities of aquatic species are generally lower, with most substrates tested, than the hepatic enzymes of mammals (40). The mixed function oxidase enzymes in marine organisms are inducible by hydrocarbons, such as 3-methylcholanthrene or benzo[a]pyrene. Moreover, it is known... 

In an effort to characterize further the metabolism of DEHP by trout, the effect of the mixed function oxidase inhibitor, piperonyl butoxide, upon the metabolism of DEHP by these trout liver fractions and serum was examined. Because of the use of piperonyl butoxide as an insecticide synergist, it is possible that fish might be exposed to this chemical in the environment. The data in Table VII show that piperonyl butoxide inhibited overall metabolism of DEHP by liver homogenates and microsomes whether NADPH was added or not. The hydrolysis of DEHP by serum was also blocked by piperonyl butoxide and although not shown, this was also the case with liver cytosol. These latter results were surprising because piperonyl butoxide has been known as a mixed function oxidase inhibitor only, and would not be expected... 

Molinate Metabolism in Carp Hepatic Mixed-function Oxidase System. Incubation of molinate with carp liver microsomes produced four major organosoluble metabolites (molinate sulfoxide, 3- and 4-hydroxy molinate, and keto HMI). Parameters affecting... 

Quantitation and Identification of 11>C-labeled Metabolites. In the iji vitro microsomal mixed-function oxidase system,... 

In water containing fish, 4-keto molinate constituted 36.8% of all organosoluble metabolites 4 days after molinate addition. However, in the in vitro microsomal mixed-function oxidase system 4-hydroxy molinate was a principal metabolite (14.3%) and 4-keto molinate represented only 0.16% of the total metabolites. Keto-HMI (2.71%) also constituted a substantial proportion of the identified metabolites. 

The biotransformation systems involved in insecticide metabolism have been studied in the R and S populations to determine any differences which might be potential contributory factors to or results of insecticide resistance. In addition, the possibility of mixed-function oxidase induction has been investigated. Specifically, the studies have encompassed a seasonal study of microsomal mixed-function oxidase (mfo) components, and studies of aldrin, dieldrin and DDT metabolism. 

Seasonal Study of Mixed Function Oxidases.— A seasonal study of hepatic microsomal mfo components has been conducted in female R and S fish (submitted for publication). Components studied were cytochromes P-450 and 5, NADPH-cytochrome c reductase, NADPH-dichlorophenolindophenol reductase, NADH-cytochrome c reductase and NADH-cytochrome 5 reductase. All were monitored at 30°C by standard spectrophotometric methods following optimization procedures (8, 9 > 10, n, J 2). Microsomal and total hepatic protein (137 and liver weight to body weight ratios were also monitored. 

Stanton, R.H. and Khan, M.A.Q. Components of the mixed-function oxidase of hepatic microsomes of fresh water fishes. Gen. Pharmac. (1975) 6, 289-29 +. 

Hepatic microsomal mixed-function oxidase activity of several marine species from coastal Maine. Drug Metab. Dispos. 

Bend, J.R., Pohl, R.J., Davidson, N.P. and Fouts, J.R. Response of hepatic and renal microsomal mixed-function oxidases in the little skate, Ra.ja erinacea, to pretreatment with 3-methyl-cholanthrene or TCDD (2,3,7,8-tetrachlorodibenzo- -dioxin). Bull. Mt, Desert Is. Biol. 

Hepatic microsomal and solubilized mixed-function oxidase systems from the little skate, Baja erinacea, a marine elasmobranch. In Ullrich, V., Hildebrandt, A., Roots, I., Eastabrook, R.W. (Eds.) Microsomes and Drug Oxidations (1976). Pergamon Press, Oxford, pp 16O-I69. 

Burns, K.A. Microsomal mixed function oxidases in an estuarine fish, funduLus heteroclitus, and their induction as a result of environmental contamination. Comp. Biochem. Physiol. (1976) 53B, l l 3- + +6. 

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